Sickle cell mouse models are hot!

The development of ingenious mouse models of sickle cell disease by variable loss or removal of mouse globin genes and transgenic introduction of human α and β^Sand/or β^S-Antilles globin genes has profoundly improved the opportunities to understand the complex pathophysiology of the sickling disorders as well as to develop new therapies. It is vital, however, to validate these models by comparison to human sickle disorders. This is especially important for nonhemoglobin abnormalities that may both reflect and contribute to the chronic hemolysis, vascular occlusion, and organ damage so characteristic of these disorders. Thus, the study by Belcher and colleagues (page 3953) is very important because it demonstrates variable increases in markers of systemic inflammation in 4 different mouse models of sickle cell anemia. Among their findings are variable elevations in leukocyte counts, serum amyloid P-component levels (an acute phase protein related to C-reactive protein), and IL-6 levels. Animals also demonstrated evidence of large and small blood vessel endothelial activation, with increased lung VCAM, ICAM, and PECAM-1, as well as increased expression of lung nuclear factor kappa B (NF-κB). Because humans with sickle cell disease demonstrate similar evidence of variably increased markers of systemic inflammation, these data help to validate the mouse models. Moreover, because leukocytosis in humans with sickle cell disease is a risk factor for disease severity and stroke, and because leukocytes and activated endothelial cells have been implicated in contributing to vascular occlusion, additional studies of these models are likely to provide both new insights into the pathophysiology of sickle cell disease, including the processes that link the hemoglobin abnormality to the inflammatory response, and opportunities to test novel therapeutic interventions.